The broad objective of the proposed research is to elucidate the binding of metal complexes to synthetic and naturally occurring polynucleotides. Three classes of metal compounds will be investigated. The first is the metallointercalation reagents, originally studied in our laboratory, that bind to double helical nucleic acids by inserting between adjacent base pairs and unwinding the duplex. Electron dense metallointercalators, such as ((terpy)Pt(SCH2CH2OH))ion, will be used to probe the structural details of the intercalation process by fiber x-ray diffraction, electron-microscopic, and other physical techniques. New metallointercalators will be synthesized and characterized, including fluorescent and paramagnetic complexes, the properties of which can be used to probe further the nature of the binding and its dependence on the conformation and base composition of nucleic acids. Metal complexes in the second class are those having high binding preferences for specific, base-determined sites in the polynucleotide. The selectivity of attachment will be achieved by enzymatically substituting a terminal sulfur atom for oxygen at the 5'-phosphate group of one of the bases, and using a class b (or soft) heavy metal that prefers to coordinate to sulfur over all other potential ligands in the polynucleotide. The labelled polynucleotide will then be studied in the electron microscope with the aim of achieving sufficient resolution and contrast for sequence determination. The design, synthesis, and characterization of heavy metal complexes and clusters with high sulfur binding specificity are related aims. The last class of metal complexes is the platinum antitumor drugs, such as cis-(Pt(NH3)2Cl2) and the pyrimidine blues. These clinically important compounds are hypothesized to exert their carcinostatic activity by strong, selective, irreversible binding to cellular DNA.